The prognosis of liver transplanted (LT) patients with recurrence of hepatocellular carcinoma (HCC), especially those with progression after locoregional treatment or advanced HCC, remains poor. Current treatment modalities involve tyrosine kinase inhibitors (TKIs) characterized by a low response rate and often poor tolerability. Encouraging findings from the Imbrave 150 study, demonstrating increased survival rates coupled with favorable treatment tolerance, prompt the investigators to consider the potential of offering the combination of treatment with Atezolizumab-Bevacizumab (Atezo-Beva) to patients with LT. No data regarding the safety and efficacy of this new combination are available for patients with LT as they were not included in Imbrave 150. Immunosuppression after LT is low when compared to essentially all other organ recipients, liver recipients are considered with lower immunological risk. However, the use of ICIs has been associated with a risk of hepatic rejection in LT patients. In this study, in order to prevent acute cellular rejection (ACR) occurrence, we propose to adopt a standardized immunosuppressive regimen closed to the one used immediately after LT but with lower therapeutic goals for tacrolimus and everolimus to allow immunotherapy treatment to be effective. The better tolerance of liver grafts will probably lead to less risk of rejection with Atezo-Beva than in other organ transplants.
Open-label multicentric single-arm two-stage phase 2 trial. Population: Adult LT patients with advanced HCC recurrence with indication to systemic treatment Primary objective: To study the safety (ACR on histology) at 6 months of the first-line Atezo-Beva combination in LT patients with recurrent HCC in association with a standardized immunosuppressive treatment to prevent the risk of liver graft rejection. Primary endpoint: Rate of Acute cellular rejection (ACR) (defined by a Histological Banff score ≥ 5) at 6 months (confirmed by an external expert center). Secondary objective: To study the safety (ACR on histology) at 24 months and at the end of Atezo-Beva treatment in LT patients with recurrent HCC in association with a standardized immunosuppressive treatment to prevent the risk of liver graft rejection. * To assess the efficacy and tolerance of first-line Atezo-Beva combination in LT patients with advanced HCC in association with a standardized immunosuppressive treatment to prevent the risk of ACR based on: * the Progression Free Survival (PFS) * the Overall survival (OS) * the objective response rate (ORR) (complete and partial response) * the duration of response * the quality of life of the patients under Atezo-Beva treatment * To compare the efficacy (OS and PFS) of LT patients treated by Atezo- Beva treatment to an historical retrospective cohort of LT patients already available treated by TKI as first line (external arm comparison) * To assess the adverse events related to Atezo-Beva treatment in LT patients with recurrent advanced HCC. * To assess the evolution of the level of donor specific antibodies (DSA) during Atezo-Beva treatment and its association with ACR, PFS and OS. Translational research/ancillary studies: * To assess the association before the first injection between the risk of ACR, PFS, OS and side effects and * the "Immunome" imaging on tumor sample and non-tumoral liver sample to quantify and regionalize immune populations on pathology (Multispectral Imaging, Mantra) * the Leukocyte DNA analysis to identify constitutional genetic variants * To assess the association before the first injection or just before the second injection and at 3 months between the risk of ACR, PFS, OS and side effects and * the "immunomonitoring" on blood sample (frequency and/or the phenotype of circulating immune cells) * the presence of tumors cells (liquid biopsies) * the presence of circulating tumor DNA and the type of mutations * the presence of circulating proteins * the profile of circulating exosomes
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Atezolizumab-Bevacizumab every 3 weeks until progression or side effects in combination with Standardized immunosuppressive treatment: Tacrolimus (objective 5-7 ng/ml) Mycophenolate Mofetil 1000 mg per day Corticosteroids at least 5 mg per day Everolimus will be continued if already started before the inclusion (objective 5-7 ng/ml). If everolimus has not been started prior to inclusion, do not start it, but adopt the following protocol: corticoids + Tacrolimus + Cellcept.
Hôpital Beaujon
Clichy, France
RECRUITINGHôpital Henri-Mondor
Créteil, France
RECRUITINGHôpital Claude Huriez - CHU de Lille
Lille, France
RECRUITINGLyon - Hôpital Croix Rousse
Lyon, France
RECRUITINGCHU Montpellier - Hôpital Saint Eloi
Montpellier, France
RECRUITINGHôpital Pitié-Salpêtrière
Paris, France
RECRUITINGCHU Rennes - Hôpital Pontchaillou
Rennes, France
RECRUITINGHôpital de Hautepierre - Strasbourg
Strasbourg, France
RECRUITINGCHU Tours - Hôpital Trousseau
Tours, France
RECRUITINGHôpital Paul Brousse
Villejuif, France
RECRUITINGRate of Acute cellular rejection (ACR) (defined by a Histological Banff score ≥ 5) at 6 months (confirmed by an external expert center)
To study the safety (ACR on histology) at 6 months of the first-line Atezo-Beva combination in LT patients with recurrent HCC in association with a standardized immunosuppressive treatment to prevent the risk of liver graft rejection
Time frame: 6 months
Rate of Acute Cellular Rejection (ACR) at 24 months
Rate of ACR (defined by a Histological Banff score ≥ 5) at 24 months (confirmed by a second external expert center.
Time frame: 24 months
Rate of Acute Cellular Rejection (ACR) at the end of Atezo-Beva treatment
Rate of ACR (defined by a Histological Banff score ≥ 5) at 24 months and at the end of Atezo-Beva treatment (confirmed by a second external expert center.
Time frame: at the end of treatment
Progression Free Survival (PFS)
The Progression Free Survival (PFS) is defined as the time from inclusion to disease progression according to RECIST 1.1 on imaging (CT-scan) performed every 3 months or death from any cause, whichever occurred first.
Time frame: between the inclusion and 24 months after the last inclusion
Overall survival (OS)
The Overall survival (OS) defined by the time from inclusion to death from any cause
Time frame: between the inclusion and 24 months after the last inclusion
Objective Response Rate (ORR)
The Objective Response Rate (ORR) at 12 months is defined as the percentage of patients with a confirmed complete or partial response according to RECIST 1.1 criteria on imaging (CT-scan) performed every 3 months.
Time frame: 12 months
Duration of response
The Duration of response is defined by the time from first documentation of complete or partial response to disease progression or death according to RECIST 1.1 criteria on imaging (CT-scan) performed every 3 months.
Time frame: between the inclusion and 24 months after the last inclusion
Time to deterioration of quality of life
The time to deterioration of quality of life is defined as the time from inclusion to the first deterioration of quality of life as reported by the patient, with deterioration defined as a decrease from baseline of 10 points or more on the EORTC QLQ-C30 maintained for two consecutive assessments or a decrease of 10 points or more in one assessment followed by death from any cause within 3 weeks. Each quality of life evaluation will be reported by the patient using EORTC QLQ-C30 score fill formed every 6 months until 24 months after the initiation of the treatment.
Time frame: between the inclusion and 24 months after the last inclusion
Type, frequency and severity of adverse events and serious adverse events
They will be assessed on the basis of the nature, frequency and severity of adverse events according to NCI Common Terminology Criteria for Adverse Events, version 4.0. The management of side effects usually observed under immunotherapy will be managed according to the American Society of Clinical Oncology Clinical Practice Guidelines
Time frame: between the inclusion, at the end of Atezo-Bev treatment and up to 24 months
Donor Specific Antibodies (DSA) median
DSA will be assessed and correlation to ACR, the PFS and OS will be evaluated
Time frame: baseline and at Day 21, 3 Months 6 Months , 12 Months , 18 Months , 24 Months
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